The worldwide chronic skin wound market, which includes diabetic foot ulcers, venous stasis ulcers and bedsores, is estimated to bear over $6 billion annually in treatment costs. The number of patients is about 12.5 million. The largest proportion is the venous stasis market, estimated at $3 billion annually, or 3.6 million patients. Venous leg ulcers are a type of chronic wound that affects up to 1 million people in the U.S., 90% of whom are over age 50. Skin lesions also present for medical treatment following accidents that involve abrasion or burning of the dermis.
Pharmaceuticals under development for managing these conditions include compositions that promote activity of endogenous cells at the site of the wound.
The family of keratinocyte growth factors has been implicated in the process of wound healing. Beer et al. (J. Investig. Dermatol. Symp. Proc. 5:34, 2000) showed that KGF is weakly expressed in healthy human skin, but strongly upregulated in dermal fibroblasts after skin injury. Binding to a transmembrane receptor on keratinocytes induces both proliferation and migration of the cells, and protects them from toxic effects of reactive oxygen species. Soler et al. (Wound Repair Regen. 7:172, 1999) characterized KGF-2 as a potential wound healing agent. It was found to increase both proliferation and migration of keratinocytes, and promote healing of human meshed skin explanted grafts and surgical excisions.
U.S. Pat. Nos. 5,814,605 and 5,965,530 provide pharmaceutical compositions comprising keratinocyte growth factor (KGF-1), for use in reducing hair loss. U.S. Pat. No. 6,077,602 relates to the sequence of keratinocyte growth factor 2 (KGF-2) and variants with enhanced activity and stability, for use in promoting wound healing. KGF-2 is currently being evaluated in clinical trials for treating injuries and skin disorders.
Other options that have been proposed for promoting activity in cells near the wound include the following. U.S. Pat. No. 5,718,897 outlines a method of enhancing migration and proliferation of keratinocytes in wound healing, by treating the wound with collagenase and a growth factor. U.S. Pat. No. 5,997,863 outlines a method of enhancing wound healing by administering enzymes that degrade glycosaminoglycans such as heparin or chondroitin sulfate in various combinations. Inada et al. (Am. J. Pathol. 157:1875, 2000) propose to facilitate wound healing by activating the transglutaminase-1 gene. Jaakkola et al. (Gene Ther. 7:1640, 2000) used adenovirus to deliver the gene for growth factor inducible element named “FIRE” into wound margin keratinocytes. U.S. Pat. No. 6,001,805 provides a method of enhancing wound healing by stimulating fibroblast and keratinocyte growth in vivo using amphipathic peptides. U.S. Pat. No. 6,191,110 outlines a method of enhancing wound healing by stimulating fibroblast and keratinocyte in vivo using amphipathic peptides of a particular sequence.
Other compositions for promoting wound healing including isolated cells and cell matrices derived from the subject being treated or a third-party donor, and adapted to provide protection of the wound while healing takes place.
U.S. Pat. No. 5,980,888 relates to a biomaterial designed for treating skin wounds, in which keratinocytes are attached to microcarrier beads of 50-500 microns in diameter. International Patent Publication WO 97/08295 outlines a reconstituted skin, comprising a dermal matrix inoculated with epithelial cells or their progenitors. U.S. Pat. No. 5,861,153 outlines a skin equivalent, comprising a support, isolated keratinocytes, and Langerhans' cells that have been activated by culturing with keratinocytes or growth factors. U.S. Pat. No. 5,580,781 reports a method for treating a skin defect by applying epidermal tissue comprising cultured outer root sheath cells. U.S. Pat. No. 6,110,208 outlines an artificial human skin comprising a support comprising a microperforated membrane upon which keratinocytes have been seeded, and an underlying tissue upon which fibroblasts have been seeded.
Genetically modified epithelial cells have been investigated in several contexts. U.S. Pat. Nos. 4,868,116, 4,980,286, and 5,698,436 relate to the introduction and expression of foreign genetic material in epithelial cells. International Patent Publication WO 97/23602 outlines techniques for obtaining human skin cell lines that have been immortalized with the SF40 large T antigen, or the E6/E7 gene of HPV16.
In 1998, Organogenesis received FDA marketing clearance for its full-thickness artificial skin product, Apligraf®, for treating venous stasis wounds. Like human skin, the product has two primary layers, an outer epidermal layer made of living human keratinocytes, the most common cell type of the human epidermis, and an inner dermal layer consisting of living human fibroblasts, the most common cell type in the human dermis. The human keratinocytes and fibroblasts used in its manufacture are derived from donor tissue. Apligraf® is currently approved for treating venous leg ulcers and diabetic foot ulcers.
The considerable complexity of the wound healing process is reviewed in Science magazine (P. Martin, Science 276:75, 1997). The article takes the view that normal adult wound repair is less like patching and more like regeneration. In view of the pervasive presence of skin lesions in our aging population, there is a compelling need for new modalities in wound healing.